Melanoma

Edward Buckingham, M.D.

Combined Plastics & Otolaryngology

Conference

The University of Texas Medical Branch

September 6, 2000

Melanoma - Outline

• General statistics and development

• Risk factors and patient assessement

• Pathology and prognosis

• Work-up and staging

• Surgical treatment

• Lymph node controversy/sentinel node

• Adjuvant therapy

Melanoma - Data

• Incidence increase fastest

• Mortality increase 2nd only to lung

• 5th most prevalent, incidence 7%/year

increase

• 5% skin cancer, 75% skin cancer death

• 1/75 in 2000, 1/1500 in 1935

• 20% H&N, 51% facial, 26% scalp, 16%

neck, 9% ear

Development of Nevi

• Melanocytes

– dendritic, neural crest, basal cell layer

– synthesis of melanin

– 1/10 to keratinocytes

– hyperplasia- tanning/lentigines, increased ratio

• Nevus transformation

– poorly understood

– dendritic- rounded

– no longer lentigionous pattern- nests

Development of Nevi

• Junctional nevi

– nests along dermal-epidermal junction

• Compound nevi

– “invade” dermis, first as nests then cords and

single cells

• Dermal nevi

– junctional component lost

Evolution of Nevi

Melanocyte Hyperplasia

Junctional Nevi

Compound Nevi

Dermal Nevi

Developement of Melanoma

• Questionable

– benign melanocytes

– progressive hyperplasia/dysplasia

• Radial growth

– in epidermis, lines of radii, no expansive nests

or nodules

– slow unrestricted , no metastatic potential

Development of Melanoma

• Vertical growth

– vertically into dermis

– expansive and coalescent nests and nodules

– metastatic potential dermal lymphatic and

vascular invasion

• Growth patterns

– biphasic- slow radial months to years- rapid

vertical growth

– monophasic- rapid vertical growth only

Evolution of Melanoma

Dysplastic Nevi

• border melanocytic nevi and malignant

melanoma

• clinical resembles malignant melanoma

• lentiginous compound nevus, prominent

bridging across rete ridges

• aberrant in inter-rete spaces

• lamellar fibrosis of papillary dermis,

variable lymphoid response

Dysplastic Nevi

Dysplastic Nevi

Types of Melanoma

• Acral lentiginous

• Mucosal melanoma

• Superfical spreading melanoma

• Lentigo maligna melanoma

• Nodular melanoma

Superficial spreading

• most common head and neck, 50%

• 4th to 5th decade

• clinical mixture of brown/tan, pink/white

irregular borders, biphasic growth

• irregular nests in epidermis

• underlying lymphoid infiltrate

• enlarged nests and single cells in all

epidermal layers

Superficial spreading

Lentigo maligna

• 20% of head and neck

• longest radial growth phase >15 yrs

• elderly sun exposed areas

• clinical dark, irregular ink spot

• contiguous lintiginous proliferation,

dyshesive, variable shape, atrophic

epidermis, infundibular basal cell layer of

hair follicles

Lentigo maligna

Nodular melanoma

• 30% of head and neck

• 5th decade

• aggressive monophasic growth

• sun-exposed and nonexposed areas

• well circumscribed blue/black or nodular

with involution in irregular plaque

• downward tumorigenic growth, expand

papillary dermis into reticular dermis

Nodular melanoma

Mucosal melanoma

• 8% head and neck

• histologic staging little use

• local control predicts survival

• neck dissection for clinical N+

• XRT for histo N+

• adjuvant interferon alpha 2-b

Risk factors

• Type I or II skin

• atypical and congenital nevi

• actinic skin changes

• history of melanoma

• family history of melanoma, atypical nevi

• history of significant sun exposure

(blistering)

Clinical

• early, increase in size, change in shape or

color of pigmented lesion

• most common symptom pruritis

• late, tenderness, bleeding, ulceration

• ABCDE’s (asymmetry, border, color,

diameter, elevation, surrounding tissue)

• Epiluminescence microscopy (ELM)

Biopsy

• excisional biopsy or saucerization if small

• incisional if large

• Depth of biopsy must be to sub-Q fat

• if melanoma a second excision must be

performed

Pathology

• diagnosis, tumor thickness in millimeters,

margins

• histologic subtype, anatomic site, Clark

level, mitotic rate, growth phase, ulceration,

regression, lymphocytes, angiolymphatic

spread, neurotropism, microsatellitosis,

precursor lesion

Prognosis

• Breslow (thickness in millimeters) strongest

predictor

Prognosis

• Clark level less predictive, thin skin useful

Prognosis

• anatomic site, ulceration, gender, histologic

type, nodal disease

• head and neck- scalp worse

• extremity better trunk

• women better men

• lymph node +

– Breslow thickness, ulceration, # pos. nodes

– Cohen 10 yr survival # nodes positive

Work-up

• H&P

– entire skin, inguinal, axillary, supraclavicular,

H&N nodes,especially primary drainage

– brain, bone, GI, constitutional symptoms

– palpable nodes FNA

• Labs and imaging

– vary, CXR to routine CT chest and LFT

– H&N CT neck routine

– If stage III(regional) or IV (distant) - CT head,

chest, abdomen, pelvis

Work-up

• FDG-PET

– some use in distant disease

– sensitivity 17% in study with SLN biopsy

Staging-Clark

• Level I - in situ at basement membrane

• Level II - through basement membrane

into papillary dermis

• Level III - spread to papillary/reticular

interface

• Level IV - spread to reticular dermis

• Level V - sub-Q invasion

Staging-Breslow

• <0.76 mm - thin

• 0.76 - 1.49 - intermediate

• 1.50 - 4.00 - intermediate

• >4.00 mm - thick

Staging

• CS/PS (I, II, III)

• AJCC- Stage I and II - local, III - regional

IV - distant

AJCC Staging

Surgical Treatment

• Recommended margins vary

• Rule of thumb

– <1mm then 1 cm

– 1-4mm then 2 cm

– >4mm then 3 cm

• All depths to underlying muscle fascia

Nodal Disease

• CS-II remove regional lymphatics

depending on location of primary and

presence of distant metastasis

CSI- The Debate

• Balch study- nonrandomized

– 5 and 10 yr survival intermediate thickness

(0.76-3.99) doubled with ELND

– 5 and 10 yr survival for thin (<0.76) and thick

(>4.0) no change with ELND

Balch Study

CSI - The Debate

• Four prospective randomized trials

– Mayo clinic 3 groups stage I (ELND, delayed,

none) no survival difference, increased

complications if none, criticized not looking at

subgroups to benefit

– WHO no survival benefit, criticized no

subgroups, largely extremity lesions in females

CSI - The Debate

• Four prospective randomized trials

– Balch - no overall 5 yr difference, improved in

patients , 60 yrs with ELND, 1-2 mm tumors,

no ulceration, or both benefited,

– WHO trunk 1.5 mm or more immediate or

delayed no significant survival benefit, however

was between ELND with occult metastasis and

later developers with delayed LND

The Debate - PRO ELND

• sequential dissemination theory

• 30% stage I & II occult disease

• Once palpable 70-80% distant disease, 10 yr

survival 15-25%, 5 yr 1-2 nodes

micrometastasis 65%

• Balch’s non-randomized study

The Debate - CON ELND

• randomized trials

• 70% no occult disease

• sequential dissemination only theory

Balch’s recommendations

• Three groups

– local, local plus micro, local plus distant

• Thin - 95% cure rate no benefit to ELND

• Intermediate - 60% regional, 20% distant,

benefit ELND

• Thick - >60% regional, >70% distant, no

benefit

• Should consider other factors as well

Sentinel Node Theory

• Essence of debate to identify those with

occult metastasis

• Morton- first node in group to receive flow

from tumor site

SLN - procedure

• isosulfan blue injection at tumor site, follow

channels to node

– studies with ELND 80% sensitivity, specificity

99%

• preoperative lymphscintigraphy, intra-

operative radiolymphoscintigrapy, and

isosulfan blue dye

– 69.5% SLN excised blue dye, 83.5% “hot”,

combined success 96%, location matters

SLN - Utility

• prognostic indicator - study SLN status

most significant indicator of disease-free

and disease-specific survival

• pathology

– H&E, S-100, HMB-45 limited by # sections

– reverse transcription with polymerase chain

reaction (RT-PCR)- peripheral blood and

nodes, (mRNA tyrosinase) 29 ELND 38% path

positive, 66% RT-PCR positive

Adjuvant Therapy

• Radiation

– high dose (400-500 cGy) bulky, residual,

recurrent, unresectable, ill

– lentigo maligna 5 yr cure 80% (disfiguring,

debilitating location)

– adjuvant- trend toward improved regional

control in N+ dissected necks

– palliate - especially bony mets

Adjuvant Therapy

• Chemotherapy

– response 25%, durable control 1%

– consider in CSI with >1.5 mm, CSII with WLE,

TND

– no survival advantage demonstrated

– single agent dacarbazine (DTIC)

– multiple combinations carmustine, cisplatin,

DTIC, tamoxifen

Adjuvant Therapy

• Immunotherapy

– unusual behavior, no survival benefit

• Interferon

– ECOG 1684, >4mm or N+, 6.9 yrs high dose

IFN-alpha-2b, improved disease-free and

overall survival approx. 1 yr. 26% dropout rate

toxicity

Summary

• Incidence and deaths on rise

• Survival rates increasing due to detection

and thorough treatment

• Depth and nodal status most important

prognostic indicators

• ELND still debated

• SLD useful

• Other modalities therapy further research